Newly discovered small molecules can disrupt the amyloid tangles that cause Alzheimer's disease

Using a molecule found in green tea, UCLA scientists have discovered other molecules that break down protein tangles in the brain that are thought to cause Alzheimer's disease and similar diseases
.

EGCG is known to destroy tau fibers — a long, multilayered fiber that tangles and attacks neurons, causing them to die
.

In a paper published in Nature Communications, UCLA biochemists describe how EGCG breaks tau fibers layer by
layer.

Thousands of J-shaped tau molecular layers bind together to form an amyloid fibrils
called "tangles.

David Eisenberg, a professor of chemistry and biochemistry at UCLA, said, "If we can break down these fibers, we might be able to stop the death
of neurons.

EGCG has been extensively studied, but has never been used as a drug to treat Alzheimer's disease because it works best in breaking down tau fibers in water and does not easily enter cells or brains
.

To study the mechanism by which EGCG breaks down tau protein fibers, the researchers extracted tau protein tangles from the brains of people who died of Alzheimer's and incubated them with EGCG at different times
.

Images of EGCG-induced mid-degradation fibrils were snap-frozen, and images of these frozen samples showed how EGCG broke fibrils into distinctly harmless fragments
.

"The EGCG molecule binds to each layer of fiber, but the molecule wants to be closer
.

Kevin Murray, then a PhD student at UCLA and now working in the Department of Neurology at Brown University, discovered specific locations
called pharmacophores on tau fibers to which EGCG molecules are attached.

"Using UCLA's supercomputing resources, we can sift
through a large library of drugs before any wet lab experiments are needed," Murray said.

Some of these top compounds, most notably molecules called CNS-11 and CNS-17, also stop fibers from spreading from cell to
cell.

"For cancer and many metabolic diseases, understanding the structure of disease-causing proteins has led to effective drugs
that block the causative effects," Eisenberg said.

CNS-11 is not yet a drug, but the authors call it a pilot
.

Eisenberg said: "By studying the changes in this substance, we are doing this, and we may extract a very good drug
from this substance.

Original:

“Structure-based discovery of small molecules that disaggregate Alzheimer’s disease tissue derived tau fibrils in vitro,” was funded primarily by the National Institutes of Health’s Institute of Aging, and the Howard Hughes Medical Institute.